Intermediates in producing phenoxyacetic acid derivatives and method of using the same

ABSTRACT

The present invention provides novel intermediates represented by general formula (I) etc. for preparing a phenoxyacetic acid derivative represented by general formula (X) or a pharmaceutically acceptable salt thereof, which has β3-adrenoceptor stimulating activity and are useful for treating or preventing obesity, hyperglycemia, diseases caused by intestinal hypermotility, pollakiuria, urinary incontinence, depression or biliary calculus. The present invention also provides a process for preparing said intermediates and a method of using said intermediates.

TECHNICAL FIELD

The present invention provides novel intermediates for preparing aphenoxyacetic acid derivative represented by general formula (X):

wherein R¹ is a lower alkyl group, or a pharmaceutically acceptable saltthereof, which has β3-adrenoceptor stimulating activity and are usefulfor treating or preventing obesity, hyperglycemia, diseases caused byintestinal hypermotility, pollakiuria, urinary incontinence, depressionor biliary calculus. The present invention also provides a process forpreparing said intermediates and a method of using said intermediates.

BACKGROUND ART

WO2000/02846 discloses a process for preparing a phenoxyacetic acidderivative represented by general formula (X), which comprises the stepof treating an amine of formula (IX):

with an alkylating agent represented by general formula (XI):

wherein R⁴ is a lower alkoxy group, R⁵ and R⁶ are a lower alkyl group, Yis an eliminating group such as a p-toluenesulfonyloxy ormethanesulfonyl group, a chlorine, bromine or iodine atom and the like,in the presence or absence of a base. However, WO2000/02846 does notteach or suggest a compound represented by general formula (I) of thepresent invention.

DISCLOSURE OF THE INVENTION

The present inventors have intensively investigated a novel intermediatewhich can be transformed into a phenoxyacetic acid derivative of generalformula (X) or a pharmaceutically acceptable salt thereof convenientlyand in high yield, and found that the phenoxyacetic acid derivative (X)can be prepared from a novel hemiacetal compound represented by generalformula (I) in very high yield. Moreover, the present inventors havefound a process for preparing the hemiacetal compound (I) from2,5-xylenol through convenient procedures. Based on these findings, thepresent invention has been accomplished.

The present invention therefore provides:

-   (1) a compound represented by general formula (I):

wherein each of R¹ and R² is independently a lower alkyl group;

-   (2) the compound according to the above (1), wherein R¹ and R² are    an ethyl group;-   (3) A process for preparing a compound represented by general    formula (I):

wherein each of R¹ and R² is independently a lower alkyl group, whichcomprises the steps of

(a) treating a compound represented by formula (II):

with a compound represented by general formula (III):

wherein R³ is a lower alkyl group, to form a compound represented bygeneral formula (IV):

wherein R³ is as defined above;

(b) treating said compound represented by general formula (IV) with acompound represented by general formula (V):ZCH₂CO₂R¹  (V)wherein Z is a chlorine, bromine or iodine atom, and R¹ is as definedabove, to form a compound represented by general formula (VI):

wherein R¹ and R³ are as defined above;

(c) reducing said compound represented by general formula (VI) to form acompound represented by general formula (VII):

wherein R¹ and R³ are as defined above;

(d) hydrolyzing said compound represented by general formula (VII) toform a compound represented by general formula (VIII):

wherein R¹ is as defined above; and

(e) treating said compound represented by general formula (VIII) withR²—OH wherein R² is as defined above;

-   (4) the process according to the above (3), wherein R¹ and R² are an    ethyl group, and R³ is a methyl group;-   (5) a compound represented by general formula (IV):

wherein R³ is a lower alkyl group;

-   (6) the compound according to the above (5), wherein R³ is a methyl    group;-   (7) a compound represented by general formula (VI):

wherein each of R¹ and R³ is independently a lower alkyl group;

-   (8) a compound represented by general formula (VII):

wherein each of R¹ and R³ is independently a lower alkyl group;

-   (9) the compound according to the above (7) or (8), wherein R¹ is an    ethyl group, and R³ is a methyl group;-   (10) a compound represented by general formula (VIII):

wherein R¹ is a lower alkyl group;

-   (11) the compound according to claim 10, wherein R¹ is an ethyl    group;-   (12) A process for preparing a compound represented by general    formula (X):

or a pharmaceutically acceptable salt thereof, wherein R¹ is a loweralkyl group, which comprises the step of treating a compound representedby general formula (I):

wherein R¹ is as defined above, and R² is a lower alkyl group, with acompound represented by formula (IX):

in the presence of a reducing agent, and thereafter optionally forming apharmaceutically acceptable salt of said compound (X)

-   (13) the process according to the above (12), wherein R¹ and R² are    an ethyl group.

In the present invention, the term “lower alkyl group” refers to astraight chained or branched alkyl group having 1 to 6 carbon atoms suchas a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl groupand the like.

BEST MODE FOR CARRYING OUT THE INVENTION

A compound represented by general formula (I) of the present inventioncan be prepared through steps (a) to (e) as illustrated in the followingscheme.

wherein R¹, R², R³ and Z are as defined above.(Step a)

A phenol derivative represented by general formula (IV) can be preparedby treating 2,5-xylenol represented by formula (II) with a compoundrepresented by general formula (III) in the presence of an aqueoussolution of alkali metal hydroxide such as an aqueous solution of sodiumhydroxide. The amount of compound (III) and alkali metal hydroxide isused ordinarily in the range of about 1 to about 3 molar equivalentsbased on 1 mole of 2,5-xylenol (II). The reaction is ordinarily carriedout at a temperature of about 10 to about 70° C. for a period of 1 to 10hours. After the reaction is finished, the reaction solution isneutralized with a dilute acid such as diluted hydrochloric acid.Thereafter, the precipitating crystals are filtered and dried to afforda phenol derivative of general formula (IV).

(Step b)

The phenol derivative (IV) is treated with a haloacetic acid ester ofgeneral formula (V) in the presence of a base in an inert solvent toafford a compound represented by general formula (VI). The inertsolvents employed in the reaction include ethers such as tetrahydrofuranor the like, ketones such as acetone, methyl ethyl ketone or the like,acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide or the like.The solvents may be used singly or as a mixture of two or more solvents.The base employed in the reaction includes sodium carbonate, potassiumcarbonate, cesium carbonate or the like. Haloacetic acid ester (V)includes ClCH₂CO₂R¹, BrCH₂ CO₂R¹ or ICH₂CO₂R¹. The amount of haloaceticacid (V) and a base is used ordinarily in the range of about 1 to about5 molar equivalents based on 1 mole of phenol derivative (IV).Haloacetic acid ester (V) and a base are ordinarily used in an equimolarratio, but either of them may be used in excess. The reaction is carriedout ordinarily at a temperature of about 0 to about 100° C. for a periodof 1 to 24 hours. After the reaction is finished, extraction of thereaction mixture and further concentration according to conventionalprocedures afford a compound of general formula (VI).

(Step c)

Reduction of the compound (VI) using a reducing agent in an inertsolvent affords an acetal derivative represented by general formula(VII). The inert solvents employed in the reaction include ethers suchas tetrahydrofuran, 1,2-dimethoxyethane, dioxane or the like, organiccarboxylic acid esters such as ethyl acetate or the like, acetonitrileor the like. The solvents may be used singly or as a mixture of two ormore solvents. Reducing agents employed in the reaction include sodiumiodide/trialkylchlorosilane such as chlorotrimethylsilane,chlorotriethylsilane, t-butyl-dimethylchlorosilane or the like, whichare ordinarily used in an amount of about 2 to about 6 molar equivalentsbased on 1 mole of compound (VI). The reaction is carried out ordinarilyat a temperature of about −30 to about 30° C. for a period of 10 minutesto 12 hours. After the reaction is finished, extraction of the reactionmixture and further concentration according to conventional proceduresafford an acetal derivative of general formula (VII).

(Step d)

Hydrolysis of the acetal derivative (VII) using an acid in a suitablesolvent affords an aldehyde derivative represented by general formula(VIII). The solvent employed in the hydrolysis reaction includes etherssuch as tetrahydrofuran, 1,2-dimethoxyethane, dioxane or the like,ketones such as acetone or the like, acetonitrile or the like. Thesolvents may be used singly or as a mixture of two or more solvents. Thesolvents may also be used in combination with water. The acid employedin the reaction includes 5-20% perchloric acid, 1-10% hydrochloric acid,1-10% sulfuric acid, p-toluenesulfonic acid, trifluoroacetic acid or thelike, which is used ordinarily in an amount of about 0.1 to about 2.5molar equivalents based on 1 mole of the acetal derivative (VII). Thehydrolysis reaction is carried out ordinarily at a temperature of about0 to about 50° C. for a period of 0.5 to 24 hours. After the reaction isfinished, extraction of the reaction mixture and further concentrationaccording to conventional procedures afford an aldehyde derivative(VIII).

(Step e)

A hemiacetal derivative represented by general formula (I) of thepresent invention can be prepared by treating the aldehyde (VIII) withR²OH, optionally in the presence of an acid such as acetic acid or thelike. The addition reaction of R²OH to the aldehyde derivative (VIII)proceeds rapidly, and the subsequent crystallization from a suitablesolvent affords a hemiacetal derivative of general formula (I). Theamount of R²OH is used ordinarily in the range of about 1 to about 10molar equivalents based on 1 mole of the aldehyde (VIII). In the case ofusing an acid, the amount of the acid is used ordinarily in the range ofabout 0.01 to about 0.1 molar equivalents based on 1 mole of thealdehyde (VIII). The solvents for crystallization include a mixedsolvent of R²OH in combination with n-hexane, n-heptane, cyclohexane orthe like. The hemiacetal derivative (I) exhibits good crystallineproperty, and can be stored under a particular condition, for examplebelow 10° C., for a long period. Accordingly, the hemiacetal aresuitable for a commercial production.

A process for preparing a phenoxyacetic acid derivative of generalformula (X), which is useful as a medicament, using a hemiacetalderivative of general formula (I) is detailed in the following scheme.

wherein R¹ and R² are as defined above.

A phenoxyacetic acid derivative represented by general formula (X) canbe prepared by treating a hemiacetal derivative of general formula (I)with an amine of formula (IX) in the presence of a reducing agent in aninert solvent. The inert solvents employed in the reaction includeethers such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane or thelike, halogenated hydrocarbons such as methylene chloride,1,2-dichloroethane or the like, organic carboxylic acids such as aceticacid or the like, hydrocarbons such as toluene or the like, alcoholssuch as methanol, ethanol or the like, acetonitrile or the like. Thesolvents may be used singly or as a mixture of two or more solvents. Thereducing agents employed in the reaction include alkali metalhydroboranes such as NaBH₄, NaBH₃CN, NaBH(OAc)₃, NaBH(OMe)₃ or the like,boranes such as BH₃.pyridine, BH₃.N,N-diethylaniline or the like. Ifnecessary, these reducing agents may be used optionally in the presenceof an acid such as acetic acid, p-toluenesulfonic acid, methanesulfonicacid, sulfuric acid, hydrochloric acid, or a base such as triethylamineor the like. Alternatively, the reaction can be carried out under ahydrogen atmosphere in the presence of a metal catalyst such as 5-10%palladium on carbon, Raney-Ni, platinum oxide, palladium black, 10%platinum on carbon (sulfided) or the like. In the case of using alkalimetal hydroboranes or boranes as a reducing agent, such reducing agentis used ordinarily in the range of about 0.5 to about 5 molarequivalents based on 1 mole of the hemiacetal derivative (I). Thereaction is carried out ordinarily at a temperature of about 0 to about60° C. for a period of 1 to 48 hours. After the reaction is finished, ifrequired, insoluble materials are filtered off, and extraction of thereaction mixture and further concentration according to conventionalprocedures afford a phenoxyacetic acid derivative of general formula(X). Alternatively, the reaction can be carried out by treating an amine(IX) with an aldehyde of general formula (VIII) in place of a hemiacetalderivative (I).

The phenoxyacetic acid derivative (X) can be optionally converted to apharmaceutically acceptable acid addition salt thereof according toconventional methods. Examples of such salts include acid addition saltsformed with mineral acids such as hydrochloric acid, hydrobromic acid,hydroiodic acid, sulfuric acid, phosphoric acid and the like; acidaddition salts formed with organic acids such as formic acid, aceticacid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, propionic acid, citric acid, succinic acid, tartaric acid, fumaricacid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid,malic acid, carbonic aid, glutamic acid, aspartic acid and the like.

An amine represented by formula (IX) can be prepared by opticallyseparating a commercially available enantiomeric mixture of the amineaccording to conventional methods. Alternatively, the amine (IX) can beprepared according to procedures as described in “J. Med. Chem., 1997,20(7), p. 978-981”.

A compound represented by general formula (I) of the present invention,its intermediates (IV), (VI), (VII) and (VIII) as well as aphenoxyacetic acid derivative of general formula (X) can be optionallyisolated or purified through standard isolation or purificationtechniques such as solvent extraction, recrystallization, chromatographyand the like.

EXAMPLE

The following examples illustrate the invention in further detail. It isto be understood, however, that they are not to be construed as limitingthe scope of the invention in any way.

Example 1 4-(1-Hydroxy-2,2-dimethoxyethyl)-2,5-dimethylphenol

A suspension of an aqueous solution of 5.2% sodium hydroxide (630 g),2,5-xylenol (100 g), an aqueous solution of 60% glyoxal dimethyacetal(213 g) and water (200 g) was heated at 55° C. for 5 hours withstirring. The reaction mixture was cooled in an ice bath, and to themixture were added acetonitrile (90 g) and 7.4% hydrochloric acid (380g) successively. The precipitating crystals were filtered to give4-(1-hydroxy-2,2-dimethoxyethyl)-2,5-dimethylphenol (150 g).

¹H-NMR(DMSO-d₆) δ ppm: 2.06 (3H, s), 2.15 (3H, s), 3.08 (3H, s), 3.35(3H, s), 4.23 (1H, d, J=6.7 Hz), 4.55 (1H, dd, J=6.7, 4.4 Hz), 4.96 (1H,d, J=4.4 Hz), 6.49 (1H, s), 7.03 (1H, s), 8.96 (1H, s)

Example 2 Ethyl2-[4-(1-hydroxy-2,2-dimethoxyethyl)-2,5-dimethylphenoxy]acetate

To N,N-dimethylformamide (81 g) were added4-(1-hydroxy-2,2-dimethoxyethyl)-2,5-dimethylphenol (20.0 g), potassiumcarbonate (15.8 g) and ethyl chloroacetate (12.4 g) at room temperaturewith stirring. The mixture was stirred at room temperature for an hour,and then stirred at 71° C. for 2 hours. The reaction mixture was dilutedwith ethyl acetate, washed with water and brine, and dried overanhydrous sodium sulfate. The organic layer was concentrated underreduced pressure, and a mixture of ethyl acetate and hexane was added tothe residue. The precipitated crystals were collected by filtration togive ethyl2-[4-(1-hydroxy-2,2-dimethoxyethyl)-2,5-dimethylphenoxy]acetate (21.3g).

¹H-NMR(CDCl₃) δ ppm: 1.28 (3H, t, J=7.1 Hz), 2.26 (3H, s), 2.32 (3H, s),2.54 (1H, d, J=2.3 Hz), 3.22 (3H, s), 3.50 (3H, s), 4.27 (2H, q, J=7.1Hz), 4.32 (1H, d, J=6.6 Hz), 4.61 (2H, s), 4.80 (1H, dd, J=6.6, 2.3 Hz),6.48 (1H, s), 7.25 (1H, s)

Example 3 Ethyl 2-[4-(2,2-dimethoxyethyl)-2,5-dimethylphenoxy]acetate

To a stirred suspension of sodium iodide (72 g) andchlorotrimethylsilane (52 g) in acetonitrile (180 g) was added dropwisea solution of ethyl2-[4-(1-hydroxy-2,2-dimethoxyethyl)-2,5-dimethylphenoxy]acetate (50 g)in acetonitrile (80 g) in an ice-salt bath. The mixture was stirred for30 minutes, and then toluene (400 g) and pyridine (25 g) were added. Thereaction mixture was washed with an aqueous solution of sodiumthiosulfate, an aqueous solution of citric acid, an aqueous solution ofsodium bicarbonate and brine successively. The organic layer was driedover anhydrous sodium sulfate, and concentrated under reduced pressureto give ethyl 2-[4-(2,2-dimethoxyethyl)-2,5-dimethylphenoxy]acetate (43g).

¹H-NMR(CDCl₃) δ ppm: 1.30 (3H, t, J=7.1 Hz), 2.24 (3H, s), 2.27 (3H, s),2.82 (2H, d, J=5.6 Hz), 3.33 (6H, s), 4.27 (2H, q, J=7.1 Hz), 4.47 (1H,t, J=5.6 Hz), 4.60 (2H, s), 6.50 (1H, s), 6.97 (1H, s)

Example 4 Ethyl 2-[4-(2-formylmethyl)-2,5-dimethylphenoxy]acetate

Ethyl 2-[4-(2,2-dimethoxyethyl)-2,5-dimethylphenoxy] acetate (23.7 g)was dissolved in acetonitrile (110 g) with stirring, and 10% perchloricacid (120 g) was added, and then the mixture was stirred for an hour atroom temperature. The reaction mixture was partitioned between toluene(190 g) and water (120 g). The organic layer was washed with water, anaqueous solution of sodium bicarbonate and brine successively, and driedover anhydrous sodium sulfate, followed by concentration under reducedpressure. After the residue was dissolved in ethanol (96 g), the solventwas removed under reduced pressure. The residue was dissolved withethanol (96 g) again, and removal of the solvent under reduced pressuregave ethyl 2-[4-(2-formylmethyl)-2,5-dimethylphenoxy]acetate (20.8 g).

¹H-NMR(CDCl₃) δ ppm: 1.30 (3H, t, J=7.1 Hz), 2.20 (3H, s), 2.25 (3H, s),3.59 (2H, d, J=2.4 Hz), 4.27 (2H, q, J=7.1 Hz), 4.62 (2H, s), 6.56 (1H,s), 6.94 (1H, s), 9.66 (1H, t, J=2.4 Hz)

Example 5 Ethyl 2-[4-(2-ethoxy-2-hydroxyethyl)-2,5-dimethylphenoxy]acetate

Ethyl 2-[4-(2,2-dimethoxyethyl)-2,5-dimethylphenoxy] acetate (43 g) wasdissolved in acetonitrile (190 g) while stirring. To the resultingsolution was added 10% perchloric acid (216 g), and the mixture wasstirred for an hour at room temperature. The reaction mixture waspartitioned between toluene (340 g) and water (200 g). The organic layerwas washed with water, an aqueous solution of sodium bicarbonate andbrine successively, and dried over anhydrous sodium sulfate, followed byconcentration under reduced pressure. The residue was dissolved inethanol (180 g), and the solvent was removed under reduced pressure. Theresidue was dissolved with hexane (86 g) and ethanol (37 g). After seedcrystals were added, the solution was stirred at 0-1° C. for 2 hours.Hexane (220 g) was added, and the resulting suspension was stirred at0-10° C. for 2 hours. The precipitated crystals were filtered to giveethyl 2-[4-(2-ethoxy-2-hydroxyethyl)-2,5-dimethylphenoxy]acetate (21 g).

¹H-NMR(DMSO-d₆) δ ppm: 1.06 (3H, t, J=7.0 Hz), 1.21 (3H, t, J=7.1 Hz),2.11 (3H, s), 2.19 (3H, s), 2.50-2.80 (2H, m), 3.20-3.40 (1H, m),3.60-3.70 (1H, m), 4.16 (2H, q, J=7.1 Hz), 4.50-4.70 (1H, m), 4.73 (2H,s), 5.98 (1H, d, J=7.6 Hz), 6.59 (1H, s), 6.93 (1H, s)

Example 6 Ethyl(−)-2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methyethyl]amino]ethyl]-2,5-dimethylphenoxy]acetate

A suspension of ethyl2-[4-(2-ethoxy-2-hydroxyethyl)-2,5-dimethylphenoxy]acetate (5.4 g), 10%palladium carbon (50% wet, 1.4 g),(1R,2S)-2-amino-1-(4-hydroxyphenyl)propan-1-ol (3.0 g) andtetrahydrofuran (30 g) was stirred under a hydrogen atmosphere at 40° C.for 3 hours. After the catalyst was removed by filtration, the filtratewas concentrated under reduced pressure. The residue was dissolved intoluene, and washed with water, an aqueous solution of sodiumbicarbonate and brine successively. The organic layer was dried overanhydrous sodium sulfate, and the solvent was removed under reducedpressure to give ethyl(−)-2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methyethyl]amino]ethyl]-2,5-dimethylphenoxy]acetate (7.3 g).

¹H-NMR(CDCl₃) δ ppm: 0.98 (3H, d, J=6.4 Hz), 1.34 (3H, t, J=7.1 Hz),2.18 (3H, s), 2.22 (3H, s), 2.60-3.00-(5H, m), 4.31 (2H, q, J=7.1 Hz),4.49 (1H, d, J=5.6 Hz), 4.62 (2H, s), 6.41 (1H, s), 6.69 (2H, d, J=8.5Hz), 6.78 (1H, s), 7.05 (2H, d, J=8.5 Hz)

Example 7 Ethyl(−)-2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methyethyl]amino]ethyl]-2,5-dimethylphenoxy]acetatehydrochloride

A suspension of ethyl2-[4-(2-ethoxy-2-hydroxyethyl)-2,5-dimethylphenoxy]acetate (68.7 g), 10%palladium carbon (50% wet, 17 g),(1R,2S)-2-amino-1-(4-hydroxyphenyl)propan-1-ol (38.0 g) andtetrahydrofuran (380 g) was stirred under a hydrogen atmosphere at 40°C. for 5 hours. After the catalyst was removed by filtration, thefiltrate was concentrated under reduced pressure. The residue wasdissolved in toluene, and washed with water, an aqueous solution ofsodium bicarbonate and brine successively. The organic layer was driedover anhydrous sodium sulfate, and the solvent was removed under reducedpressure. The residue was dissolved in toluene (200 g) and ethanol (21g), and 20 weight % hydrogen chloride in ethanol (37.3 g) was addeddropwise. The precipitated crystals were filtered to give ethyl(−)-2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methyethyl]amino]ethyl]-2,5-dimethylphenoxy]acetatehydrochloride (70.2 g).

¹H-NMR(DMSO-d₆) δ ppm: 0.96 (3H, d, J=6.6 Hz), 1.21 (3H, t, J=7.1 Hz),2.15 (3H, s), 2.25 (3H, s), 2.8-3.2 (4H, m), 4.16 (2H, q, J=7.1 Hz),4.76 (2H, s), 4.9-5.1 (1H, m), 5.8-6.0 (1H, m), 6.68 (1H, s), 6.76 (2H,d, J=8.5 Hz), 6.96 (1H, s), 7.17 (2H, d, J=8.5 Hz), 8.5-9.0 (2H, br),9.41 (1H, s)

INDUSTRIAL APPLICABILITY

Via a hemiacetal derivative represented by general formula (I) of thepresent invention, a phenoxyacetic acid derivative of general formula(X) or pharmaceutically acceptable salt thereof can be prepared from acommercially available 2,5-xylenol in high purities and throughconvenient procedures. Therefore, said hemiacetal derivative (I) isuseful as a intermediate for preparing a medicament for treating orpreventing obesity, hyperglycemia, diseases caused by intestinalhypermotility, pollakiuria, urinary incontinence, depression or biliarycalculus.

1. A compound represented by general formula (I):

wherein each of R¹ and R² is independently a lower alkyl group.
 2. Thecompound according to claim 1, wherein R¹ and R² are an ethyl group. 3.A process for preparing a compound represented by general formula (I):

wherein each of R¹ and R² is independently a lower alkyl group, whichcomprises the steps of (a) treating a compound represented by formula(II):

with a compound represented by general formula (III):

wherein R³ is a lower alkyl group, to form a compound represented bygeneral formula (IV):

wherein R³ is as defined above; (b) treating said compound representedby general formula (IV) with a compound represented by general formula(V):ZCH₂COR¹  (V) wherein Z is a chlorine, bromine or iodine atom, and R¹ isas defined above, to form a compound represented by general formula(VI):

wherein R¹ R³ as defined above; (c) reducing said compound representedby general formula (VI) to form a compound represented by generalformula (VII):

wherein R¹ and R³ are as defined above; (d) hydrolyzing said compoundrepresented by general formula (VII) to form a compound represented bygeneral formula (VIII):

wherein R¹ as defined above; and (e) treating said compound representedby general formula (VIII) with R²—OH wherein R² as defined above.
 4. Theprocess according to claim 3, wherein R¹ and R² are an ethyl group, andR³ a methyl group.
 5. A compound represented by general formula (VII):

wherein each of R¹ and R³ is independently a lower alkyl group.
 6. Thecompound according to claim 5, wherein R¹ is an ethyl group, and R³ is amethyl group.